Madopar 250, 200 mg+50 mg, tablets, 100 pcs.

Instructions for use of MADOPAR

Treatment should be started gradually, with individual doses adjusted until the optimal therapeutic effect is achieved. The following dosage regimen instructions should be considered as general recommendations.

Madopar 125 mg capsules should be swallowed whole without chewing. Madopar 250 mg tablets can be crushed to make them easier to swallow. Madopar GSS capsules should not be opened before use, otherwise the effect of the modified release of the active substance is lost.

Standard dosage regimen

Parksinson's disease

The drug should be taken at least 30 minutes before or 1 hour after meals.

Initial treatment.

At the early stage of Parkinson's disease, it is recommended to begin treatment with Madopar at a dose containing 50 mg of levodopa + 12.5 mg of benserazide 3-4 times a day. If well tolerated, the dose should be gradually increased, depending on the patient's response.

The optimal effect is achieved, as a rule, with a daily dose containing 300-800 mg of levodopa + 75-200 mg of benserazide, in 3 or more doses. It may take 4 to 6 weeks to achieve optimal results. Further increases in the daily dose, if necessary, should be carried out at intervals of 1 month.

Maintenance treatment.

The average maintenance dose is 125 mg (100 mg levodopa + 25 mg benserazide) 3-6 times a day. The frequency of administration (at least 3 times) during the day should be distributed so as to ensure optimal effect.

To optimize the effect, you can replace Madopar capsules 125 mg and tablets 250 mg with Madopar GSS.

Restless legs syndrome

The drug should be taken 1 hour before bedtime, with a small amount of food. The maximum daily dose is 500 mg Madopar (400 mg levodopa + 100 mg benserazide).

Idiopathic restless legs syndrome with sleep disturbances

It is recommended to prescribe Madopar in the form of 125 mg capsules or 250 mg tablets.

The initial dose of Madopar is 62.5 mg (50 mg levodopa + 12.5 mg benserazide) - 125 mg (100 mg levodopa + 25 mg benserazide). If the effect is insufficient, the dose of Madopar should be increased to 250 mg (200 mg levodopa + 50 mg benserazide).

Idiopathic restless legs syndrome with sleep and sleep disorders

Initial dose: Madopar GSS 1 capsule and Madopar 1 capsule 125 mg 1 hour before bedtime. If the effect is insufficient, the dose of Madopar GSS should be increased to 250 mg (2 capsules).

Idiopathic restless legs syndrome with difficulty falling asleep and staying asleep, as well as disturbances during the day

Additionally:

• Madopar 1 capsule 125 mg, the maximum daily dose of Madopar is 500 mg (400 mg levodopa and 100 mg benserazide).

Restless legs syndrome in patients with chronic renal failure receiving dialysis

The drug is prescribed in a dose of 125 mg (Madopar 1 capsule 125 mg) 30 minutes before the start of dialysis.

Dosage regimen in special cases

Parkinson's disease

Madopar can be combined with other antiparkinsonian drugs; as treatment continues, it may be necessary to reduce the dose of other drugs or gradually discontinue them.

It is better to start the transition to Madopar GSS with a morning dose, maintaining the daily dose and regimen of Madopar in the form of 125 mg capsules or 250 mg tablets.

After 2-3 days, the dose is gradually increased by approximately 50%. The patient should be warned that his condition may temporarily worsen. Due to its pharmacokinetic properties, Madopar GSS begins to act somewhat later. The clinical effect can be achieved faster by prescribing Madopar GSS together with Madopar in the form of capsules 125 mg. This may be especially useful in the case of the first morning dose, which should be slightly higher than subsequent doses. The individual dose of Madopar GSS should be selected slowly and carefully, the interval between dose changes should be at least 2-3 days. In patients with nocturnal symptoms, a positive effect was achieved by gradually increasing the evening dose of Madopar GSS to 250 mg (2 capsules) before bedtime.

To eliminate the pronounced effect of Madopar GSS (dyskinesia), increasing the intervals between doses is more effective than reducing the single dose. If Madopar GSS is not effective enough, it is recommended to return to previous treatment with Madopar in the form of 125 mg capsules and 250 mg tablets.

In patients with mild or moderate renal impairment

no dose adjustment is required.

Madopar is well tolerated by patients receiving hemodialysis sessions. With long-term therapy, episodes of “freezing”, “dose depletion phenomenon”, and “on-off” phenomena may occur. During episodes of “freezing” and the “dose depletion phenomenon,” they resort to splitting the dose of the drug (reducing the single dose or shortening the interval between doses of the drug), and when the “on-off” phenomenon occurs, they increase the single dose while reducing the number of doses. Then you can try to increase the dose again to enhance the effect of treatment.

Restless legs syndrome

To avoid an increase in the symptoms of restless legs syndrome (early appearance during the day, increasing severity and involvement of other parts of the body), you should not exceed the recommended maximum dose of Madopar - 500 mg (400 mg levodopa + 100 mg benserazide).

If clinical symptoms increase, the dose of levodopa should be reduced or levodopa should be gradually discontinued and other therapy should be prescribed.

Composition and release form

Madopar® fast-acting tablets (dispersible) “125”

in dark glass bottles 30 or 100 pcs.; 1 bottle in a cardboard pack.

Madopar® "125"

in dark glass bottles 30 or 100 pcs.; 1 bottle in a cardboard pack.

Madopar® “250”

in dark glass bottles 30 or 100 pcs.; 1 bottle in a cardboard pack.

Madopar® GSS "125"

in dark glass bottles 30 or 100 pcs.; 1 bottle in a cardboard pack.

Pharmacodynamics

Combined drug for the treatment of Parkinson's disease and restless legs syndrome.

Parkinson's disease. Dopamine, a neurotransmitter in the brain, is produced in insufficient quantities in the basal ganglia of patients with parkinsonism. Levodopa or L-DOPA (3,4-dihydrophenylalanine) is a metabolic precursor to dopamine. Unlike dopamine, levodopa penetrates well through the BBB. After levodopa enters the central nervous system, it is converted to dopamine by aromatic amino acid decarboxylase.

Replacement therapy is carried out by prescribing levodopa, the immediate metabolic precursor of dopamine, since the latter does not penetrate the BBB well.

Following oral administration, levodopa is rapidly decarboxylated to dopamine in both cerebral and extracerebral tissues. As a result, most of the administered levodopa does not reach the basal ganglia, and peripheral dopamine often causes side effects. Therefore, blocking extracerebral decarboxylation of levodopa is necessary. This is achieved by the simultaneous administration of levodopa and benserazide, a peripheral decarboxylase inhibitor.

Madopar® is a combination of these substances in an optimal ratio of 4:1 and is as effective as large doses of levodopa.

Restless legs syndrome. The exact mechanism of action is unknown, but the dopaminergic system plays an important role in the pathogenesis of this syndrome.

Use during pregnancy and breastfeeding

Madopar® is absolutely contraindicated during pregnancy and in women of childbearing age who do not use reliable methods of contraception, due to possible disruption of skeletal development in the fetus.

If pregnancy occurs during treatment, the drug should be discontinued in accordance with the recommendations of the attending physician.

If it is necessary to take Madopar® during breastfeeding, breastfeeding should be discontinued due to the lack of reliable data on the penetration of benserazide into breast milk. The risk of abnormal skeletal development in a newborn cannot be ruled out.

Interaction

Pharmacokinetic interaction

Trihexyphenidyl (an anticholinergic drug) reduces the rate, but not the extent, of absorption of levodopa. The administration of trihexyphenidyl together with Madopar® GSS “125” does not affect other parameters of the pharmacokinetics of levodopa.

Antacids reduce the degree of absorption of levodopa by 32% when prescribed with Madopar® GSS "125".

Ferrous sulfate reduces the plasma levodopa Cmax and AUC by 30–50%, which is a clinically significant change in some patients.

Metoclopramide increases the rate of absorption of levodopa.

Levodopa does not interact pharmacokinetically with bromocriptine, amantadine, selegiline and domperidone.

Pharmacodynamic interaction

Neuroleptics, opiates and antihypertensive drugs containing reserpine suppress the effect of Madopar®.

MAO inhibitors. If Madopar® is prescribed to patients receiving irreversible non-selective MAO inhibitors, then at least 2 weeks must elapse from stopping the MAO inhibitor before starting Madopar® (see “Contraindications”). However, selective MAO-B inhibitors (such as selegiline or rasagiline) and selective MAO-A inhibitors (such as moclobemide) can be prescribed to patients taking Madopar®. It is recommended to adjust the dose of levodopa depending on the patient's individual needs in terms of effectiveness and tolerability. The combination of MAO-A and MAO-B inhibitors is equivalent to taking a non-selective MAO inhibitor, therefore such a combination should not be prescribed simultaneously with Madopar®.

Sympathomimetics (adrenaline, norepinephrine, isoproterenol, amphetamine). Madopar® should not be prescribed simultaneously with sympathomimetics, since levodopa may potentiate their effect. If concomitant use is still necessary, careful monitoring of the cardiovascular system and, if necessary, reducing the dose of sympathomimetics are very important.

Antiparkinsonian drugs. The combined use of the drug with other antiparkinsonian drugs (anticholinergics, amantadine, dopamine agonists) is possible, but this may enhance not only the desired, but also the undesirable effects. It may be necessary to reduce the dose of Madopar® or another drug. If a catechol-o-methyltransferase inhibitor (COMT) is added to treatment, a reduction in the dose of Madopar® may be required. When starting Madopar® therapy, anticholinergic drugs should not be discontinued abruptly, since levodopa does not begin to act immediately.

Levodopa may affect laboratory results of catecholamines, creatinine, uric acid and glucose, and a false-positive Coombs test result is possible.

In patients receiving Madopar®, taking the drug simultaneously with a protein-rich meal may interfere with the absorption of levodopa from the gastrointestinal tract.

General anesthesia with halothane. Taking Madopar® should be discontinued 12–48 hours before surgery, since a patient receiving Madopar® may experience blood pressure fluctuations and arrhythmia during halothane anesthesia.

Side effects

From the blood system: rare cases of hemolytic anemia, transient leukopenia, thrombocytopenia. In patients taking levodopa for a long time, it is recommended to periodically monitor the blood count, liver and kidney function.

From the gastrointestinal tract: anorexia, nausea, vomiting, diarrhea, isolated cases of loss or change in taste, dryness of the oral mucosa.

On the skin: rarely - itching, rash.

From the cardiovascular system: arrhythmias, orthostatic hypotension (weakens after reducing the dose of Madopar®), arterial hypertension.

From the nervous system and mental sphere: agitation, anxiety, insomnia, hallucinations, delirium, temporary disorientation (especially in elderly patients and patients with a history of these symptoms), depression, headache, dizziness, sometimes in later stages of treatment - spontaneous movements (such as chorea or athetosis), episodes of “freezing”, weakening of the effect towards the end of the dose period (the “exhaustion” phenomenon), the “on-off” phenomenon, severe drowsiness, episodes of sudden drowsiness, increased manifestations of restless legs syndrome .

From the body as a whole: febrile infection, rhinitis, bronchitis.

Laboratory indicators: sometimes - a transient increase in the activity of liver transaminases and alkaline phosphatase, an increase in blood urea nitrogen, a change in the color of urine to red, darkening when standing.

Description of the dosage form

Dispersible tablets: cylindrical, flat on both sides with a beveled edge, white or almost white, odorless or slightly odorless, slightly marbled, engraved “ROCHE 125” on one side of the tablet and a break line on the other side. Tablet diameter is about 11 mm; thickness - about 4.2 mm.

Capsules: hard gelatin; body - pinkish-flesh color, opaque; the lid is light blue, opaque; The capsule is marked “ROCHE” in black. The contents of the capsules are a fine granular powder, sometimes clumped, light beige in color, with a subtle odor.

Tablets: cylindrical, flat with a beveled edge, pale red in color with small inclusions, with a subtle odor; on one side of the tablet there is a cross-shaped line, engraving “ROCHE” and a hexagon; on the other there is a cross-shaped risk. Tablet diameter - 12.6–13.4 mm; thickness - 3–4 mm.

Modified release capsules: hard gelatin; body - light blue, opaque; the lid is dark green, opaque; The capsule is marked “ROCHE” in rusty red ink. The contents of the capsules are a fine granular powder, sometimes clumped, white or slightly yellowish in color, with a subtle odor.

Pharmacokinetics

Suction

Madopar® “125” capsules and Madopar® “250” tablets

Levodopa is primarily absorbed in the upper small intestine. The time to reach Cmax of levodopa is 1 hour after taking capsules or tablets.

Capsules and tablets are bioequivalent.

Cmax of levodopa in plasma and the extent of levodopa absorption (AUC) increase proportionally to the dose (in the levodopa dose range from 50 to 200 mg).

Eating reduces the rate and extent of absorption of levodopa. When capsules or tablets are administered after meals, the Cmax of levodopa in plasma is reduced by 30% and is achieved later. The degree of absorption of levodopa is reduced by 15%. The absolute bioavailability of levodopa in Madopar® “125” capsules and Madopar® “250” tablets is 98% (from 74 to 112%).

Madopar® fast-acting tablets (dispersible) “125”

The pharmacokinetic profiles of levodopa after administration of dispersible tablets are similar to those after administration of Madopar® "125" capsules or Madopar® "250" tablets, but the time to reach Cmax tends to decrease. Patient absorption of dispersible tablets is less variable.

Madopar® GSS "125", capsules with modified release of the active substance

Madopar® GSS “125” has different pharmacokinetic properties than the above release forms. The active substances are released slowly in the stomach. Cmax in plasma is 20–30% less than that of conventional dosage forms and is achieved 3 hours after administration. The dynamics of plasma concentration is characterized by a longer half-life (the period of time during which the plasma concentration is greater than or equal to half the maximum) than that of Madopar® 125 capsules and Madopar® 250 tablets, which indicates a continuous modifiable release . The bioavailability of Madopar® GSS “125” is 50–70% of the bioavailability of Madopar® “125” capsules and Madopar® “250” tablets and does not depend on food intake. Food intake does not affect the Cmax of levodopa, which is achieved later, 5 hours after taking Madopar® GSS “125”.

Distribution

Levodopa crosses the BBB via a saturable transport system. It does not bind to plasma proteins. Distribution volume - 57 l. The AUC for levodopa in cerebrospinal fluid is 12% of that in plasma.

Benserazide in therapeutic doses does not penetrate the BBB. It accumulates mainly in the kidneys, lungs, small intestine and liver.

Metabolism

Levodopa is metabolized by two main pathways (decarboxylation and o-methylation) and two additional pathways (transamination and oxidation).

Aromatic amino acid decarboxylase converts levodopa to dopamine. The main end products of this metabolic pathway are homovanillic and dihydroxyphenylacetic acids.

Catechol-o-methyl-transferase methylates levodopa to form 3-o-methyldopa. The half-life of this main metabolite from plasma is 15–17 hours, and its accumulation occurs in patients taking therapeutic doses of Madopar®.

Reduced peripheral decarboxylation of levodopa when coadministered with benserazide leads to higher plasma concentrations of levodopa and 3-o-methyldopa and lower plasma concentrations of catecholamines (dopamine, norepinephrine) and phenolcarboxylic acids (homovanillic acid, dihydrophenylacetic acid).

In the intestinal mucosa and liver, benserazide is hydroxylated to form trihydroxybenzylhydrazine. This metabolite is a potent inhibitor of aromatic amino acid decarboxylase.

Removal

With peripheral inhibition of T1/2 decarboxylase, levodopa - 1.5 hours. Plasma clearance of levodopa is approximately 430 ml/min.

Benserazide is almost completely eliminated by metabolism. Metabolites are excreted mainly in urine (64%) and to a lesser extent in feces (24%).

Pharmacokinetics in special groups of patients

Patients with renal and liver failure. There are no data on the pharmacokinetics of levodopa in patients with renal and hepatic impairment.

Elderly patients (65–78 years). In elderly patients (65–78 years) with Parkinson's disease, T1/2 and AUC of levodopa increase by 25%, which is not a clinically significant change and does not in any way affect the dosage regimen.

Indications of the drug Madopar® “250”

Parkinson's disease:

— Madopar® fast-acting tablets (dispersible) “125” — a special dosage form for patients with dysphagia and akinesia in the early morning hours and in the afternoon, or with the phenomena of “depletion of the effect of a single dose” or “increase in the latent period before the onset of the clinical effect of the drug ";

— Madopar® GSS “125” is indicated for any type of fluctuation in the effect of levodopa (namely: “peak dose dyskinesia” and “end dose phenomenon”, for example, immobility at night);

restless legs syndrome, including idiopathic and restless legs syndrome in patients with chronic renal failure on dialysis.

Contraindications

hypersensitivity to levodopa, benserazide or any other component of the drug;

decompensated dysfunction of endocrine organs, liver or kidneys (except for patients with restless legs syndrome receiving dialysis);

diseases of the cardiovascular system in the stage of decompensation;

mental illness with a psychotic component;

angle-closure glaucoma;

in combination with non-selective MAO inhibitors or a combination of MAO-A and MAO-B inhibitors;

age under 25 years;

pregnancy;

breastfeeding period;

women of childbearing age who are not using reliable methods of contraception (see “Pregnancy and lactation”).